The present invention relates to two new compounds which we have isolated from newly discovered strains of microorganism of the species Penicillium, as well as to salts and esters of these compounds. We have named the new compounds "the adenophostins". The invention also provides processes for the preparation of these compounds and methods and compositions using them for the treatment and prophylaxis of a variety of diseases and disorders resulting from an imbalance in the calcium ion concentration in the mammalian body.
The novel compounds of the present invention, adenophostins A and B, have the ability to increase intracellular calcium ion concentrations by acting on the inositol 1,4,5-trisphosphate (Insp.sub.3) receptors which exist in the endoplasmic reticulum.
It is now well known that calcium ions play an important role in many cellular processes, including, for example, neural activity, muscle contraction, various secretion reactions and cellular growth and differentiation. Accordingly, the release of calcium ions into the cytosol is important to the operation of these processes, and compounds which have the ability to control this release clearly have great potential for use in therapy.
InsP.sub.3 itself has an important effect on the release of calcium ions from internal stores to the cytosol [Nature 341, 197-205 (1989)]. InsP is produced in vivo from phospholipids which exist in cellular membranes by means of phospholipase C, which, in turn, may be activated by various hormones [Nature 312, 315-321 (1984)]. The InsP.sub.3 thus produced binds to InsP.sub.3 receptors located on the endoplasmic reticulum, where calcium ions are believed to be stored [Nature 342, 32-38 (1989)]. This binding results in activation of the calcium channels in the receptor, and calcium ions stored in the endoplasmic reticulum are released to the cytosol, thus elevating the cytosolic calcium ion concentration [Nature 342, 87-89 (1989); Neuron 5, 11-18 (1990)].
Like InsP.sub.3, adenophostins A and B have the ability to bind to InsP.sub.3 receptors, to open calcium channels in cells, especially the endoplasmic reticulum, and thus to elevate the cytosolic calcium ion concentration. The presence of a high concentration of InsP.sub.3 receptors in cerebellar Purkinje cells suggests that InsP plays an important role in the development and differentiation of the nervous system [J. Neurochem. 51, 1724-1730 (1988)]. In addition, since long-term depression of the efficacy of synaptic transmission in Purkinje cells is believed to have some sort of memory function, InsP.sub.3 is thought also to participate in cerebral learning and memory [Ann. Rev. Neurosci. 12, 85-102 (1988)]. A decrease in cerebral InsP.sub.3 in patients with Huntington's disease (Huntington's chorea) has also been observed [J. Neurochem. 56, 1417-1422 (1991)], and, although a causal relationship has not been established, it is thought that administration of a compound having an activity equivalent to that of InsP.sub.3 would alleviate the condition.
In addition, since it has been demonstrated that an elevation of the InsP.sub.3 -induced peripheral intracellular calcium ion concentration causes contraction of the smooth muscles, activation of the thymus-originated lymphocytes (T cells) and activation of pancreatic secretion [Ann. Rev. Biochem. 56, 159-193 (1987): Nature 348, 66-69 (1990)], compounds having an InsP.sub.3 -like ability to open calcium channels are expected to be useful as hypertensive agents because of their contractive action on vascular smooth muscles, as immuno-activating agents because they activate the immunocompetent cells and for the treatment of type I diabetes mellitus by accelerating insulin secretion.
The adenophostin compounds of the present invention are adenosine derivatives which additionally contain a structure similar to, but different from, that of inositol phosphate.
A number of adenosine derivatives is known as microbial second metabolites. For example, agrocin [Nature, 265, 379-381 (1977)] and thuringiensin [Collection of Czechoslovak Communications, 42, 909-929 (1977)] are adenosine derivatives and include a phosphate group in the molecule, like the adenophostins, but they differ structurally from adenophostins A and B. Moreover, these compounds are reported to have different activities to those of adenophostins A and B, and there have been no reports of which we are aware suggesting that they have the same effect on InsP.sub.3 receptors as do adenophostins A and B, or that they influence release of calcium ions.
Cyclic ADP-ribose is an adenosine derivative which induces calcium ion release from intracellular calcium ion stores in a manner apparently similar to that of the adenophostins and InsP.sub.3 [The Journal of Biological Chemistry, 264, 1608-1615 (1989)]. However, it has been reported that the action of cyclic ADP-ribose is due to activation of the calcium-induced calcium release channel, not by activation of the InsP.sub.3 receptors [Science, 253, 1143-1146 (1991)]. This finding is also reinforced by the fact that the structure of cyclic ADP-ribose is different from that of the adenophostins of the present invention.
Additionally, some inositol derivatives have been synthesized and found to act on the InsP.sub.3 receptors [The Journal of Biological Chemistry, 264, 20303-20308 (1989). The Journal of the American Chemical Society, 113, 1822-1825 (1991): Tetrahedron Letters, 32, 6021-6024 (1991)], but these are not adenosine derivatives.
In summary, we are not aware of the disclosure of any adenosine derivatives, which possess an activity similar to that of InsP.sub.3.